The object of this proposal is to further develop multiple indicator dilution methods for evaluating metabolic functions of the pulmonary capillary endothelium as a means to identify and mathematically model fundamental mechanisms that affect the exchange of substrates between the blood and the endothelium in the normal and injured dog lung. One aim of the proposed studies is to identify and evaluate factors and processes in the blood that influence the interaction of biogenic amines (serotonin and norepinephrine), prostaglandins (PGE1 and PGA1) and several synthetic substrates of angiotensin converting enzyme (ACE) with the lung endothelium. In solated dog lung lobes, cellular and protein composition of the perfusate as well as substrate-perfusate and substrate-endothelium contact time will be independently varied in order to determine quantitatively the effects of transient kinetics upon the uptake and/or metabolism of these endothelial substrates. Changes in substrate- pulmonary endothelial interactions will be quantified and analyzed using kinetic model parameters for normal lungs and compared to lungs injured by treatment with small bead embolism, high vascular pressure or several agents which alter microvascular permeability in order to test the sensitivity of the kinetic parameters to different types of lung injury. To provide an independent measure perfused surface area in the lung, an important measurement in interpreting lung metabolic functions, a second aim is directed towards evaluating the volume distribution of diazepam. Diazepam, as a lipophilic indicator, is essentially excluded from the extravascular space and thus may provide an interpretable index of changes in perfused surface area. The experiments will be conducted in the intact anesthetized dog subjected to various interventions to alter pulmonary hemodynamics, perfused surface area or extravascular water. The third aim of the study is to develop mathematical models as concise expressions of hypotheses which account for the dominant physical, chemical, and physiological processes affecting the fate of the endothelial substrates identified above. These models will be used to quantitatively test the proposed hypotheses and to estimate kinetic parameters that could serve as quantifiers of pulmonary endothelial function.